Caspases are cysteine proteases so named due to strict specificity for cleaving peptide sequences C-terminal to aspartic acids residues. Currently, 12 caspase isozymes have been identified in humans with numerous reported activities. Caspases are often subcategorized as either pro-apoptotic or pro-inflammatory enzymes. A prominent member of the pro-inflammatory class is caspase 1 (also known as interleukin-converting enzyme or ICE) which is responsible for the proteolytic activation of interleukin (IL)-1β and IL-18. IL-1β and IL-18 are cytokines that play a major role in the immune response and within numerous autoimmune and inflammatory diseases. Caspase 1 is constitutively and inducibly expressed in immune response elements such as T cells, macrophages and neutrophils.
Inhibitors of caspase 1 are sought for intervention strategies within ischemic disorders, Huntington's disease, amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and sepsis. To date, at least three caspase 1 inhibitors have entered clinical evaluation including Pralnacasan (VX-740), IDN-6556 and VX-765. All three agents are active site inhibitors that act through reversible (Pralnacasan and VX-765) or irreversible (IDN-6556) covalent modification of the catalytic cysteine residue. VX-765 (compound 1) is a prodrug that require esterase cleavage of the 5-ethoxydihydrofuran-2(3H)-one moiety to yield the aldehyde functionality of the drug VRT-043198 (compound 2b) that acts as a potent electrophile for attack by the active site cysteine thiol (see FIG. 1). The remainder of the VX-765 molecule establishes key binding contacts with caspase 1 that enhance the potency of the interaction and confer a modest degree of selectivity. In 2004, Vertex Pharmaceuticals reported that VX-765 had entered a phase II clinical study targeting psoriasis. Subsequent reports on the clinical development of VX-765 have yet to be released.